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Inhibition of Ghrelin O-Acyltransferase (GOAT) by Octanoylated Pentapeptides
Jing Yang, Tong-Jin Zhao, Joseph L. Goldstein and Michael S. Brown
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 31 (Aug. 5, 2008), pp. 10750-10755
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25463233
Page Count: 6
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The discovery of ghrelin O-acyltransferase (GOAT) opens the way to the design of drugs that block the attachment of an octanoyl group to the appetite-stimulating peptide hormone ghrelin, potentially preventing obesity. Here, we develop a biochemical assay that uses membranes from insect cells infected with baculovirus encoding mouse GOAT. The GOAT-containing membranes transferred the [³H]octanoyl group from [³H]octanoyl CoA to recombinant proghrelin in vitro. Transfer depended on the serine at residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [³H]octanoyl to a pentapeptide containing only the N-terminal five amino acids of proghrelin. GOAT activity could be inhibited by an octanoylated ghrelin pentapeptide, and its potency was enhanced 45-fold when the octanoylated serine-3 was replaced by octanoylated diaminopropionic acid. The data suggest that GOAT is subjected to end-product inhibition and this inhibition is better achieved with substrates having the octanoyl group attached through an amide linkage rather than the corresponding ester. These insights may facilitate the future design of useful inhibitors of GOAT.
Proceedings of the National Academy of Sciences of the United States of America © 2008 National Academy of Sciences